Brain Organoids Provide Insight into Autism

Stem cells help reveal brain development in patients with autism spectrum disorder

Using stem cells derived from patients' skin cells, researchers have created three-dimensional neuronal cultures to mimic brain development in patients with Autism Spectrum Disorder (ASD). These so-called "brain organoids" revealed an excess of inhibitory cells and increased neuronal connections, which the scientists were then able to correct by suppressing the expression of one gene, FOXG1.

Although genetic variations and environmental factors are known to contribute to risk for ASD, about 80% of cases still lack clear etiologies or pathogenic models. By studying the growth of 3D brain cell cultures made from human stem cells, the researchers got an unprecedented look at how this disorder might arise during early fetal brain development (up to 16 weeks post conception). They studied four families that had at least one member who had ASD with an enlarged brain -- a feature associated with severe autism that occurs in about 20% of people with the disorder.

The study, conducted by researchers at Yale University, appeared today in the journal Cell. While this wasn't the first study to grow 3D neuronal cell cultures, it was the first to use this method to study idiopathic autism.

Senior author Flora Vaccarino, MD, said that this type of research is useful "because no one knows what these early cells might look like in a patient with autism." Previous similar studies have focused on disorders caused by rare genetic mutations, like Rett or Timothy syndrome. "But no one has tried to do this with a type of patient where you don't know the genetic underpinnings," like with ASD patients, she added.

Not knowing the genetics behind ASD, the researchers decided to look at how cells from different patients develop. They figured that even if the genes are not the same, there may be something in common with cell development. "Indeed, we found that there are abnormalities that are shared in neurodevelopment," Vaccarino said. The study also found that the biological measures were correlated with later developmental symptoms.

But most importantly, the scientists were able to fix the observed neuronal imbalance in their brain organoids by suppressing a single gene. This suggests that it may be possible to restore neuronal balance in living human brains via clinical intervention.

"This study provides valuable insights into autism by suggesting a bias in favor of the production of inhibitory neurons caused by a particular gene," Manuel Casanova, MD, told MedPage Today in an email. "The implications of this study and the doors it opens for future studies are incredibly large and significant."

Vaccarino said that expanding the study to include more patients and more subgroups with ASD is their next priority. "Because patients are intrinsically different, it's hard to find a common drug. But if you can more precisely sub-categorize patients with autism or other disorders, maybe it'll be easier to find treatments for a particular subgroup."

The researchers also hope to figure out exactly what caused the gene expression alterations and neuronal imbalances found in their study. It could be a genetic mutation or some other epigenetic change.

Once scientists have a better understanding of the neurobiological abnormalities in ASD and other developmental disorders, "then we can try ways to correct this with medicine," she added.

Though Casanova felt the study was incredibly important and well-done, he mentioned that it did have some limitations. Other than the small sample size, he expressed concern over the validity of using such a 3D cell culture to model an entire human brain. "The way neurons aggregate in these cultures ... may bear little resemblance to the circuitry observed in the human brain."

"Still, the idea of simplifying research in autism by studying a reductionist model of the brain is commendable."

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